Chemical Background
WO 02/49993, discloses aryl-substituted heterocyclic derivatives and the use of such compounds in treating a variety of inflammatory and immuno system disorders. U.S. Pat. No. 4,145,439 describes benzyl phenyl ethers and their use for combatting arthropodes, nematodes, fungi and bacteria. WO 03/37865 describes the preparation of pyridinylethyl amines and amides and their use as anticancer drugs. WO 01/14331 describes the preparation of 4-amino-1-benzylpiperidines(piperazines) as antimalarial agents. In U.S. Pat. No. 5,318,988 2-aminomethyl-chromanes are described together with their use in the treatment of CNS diseases. In J. Indian Chem. Soc. 1987, 64, 169-171, the synthesis of benzodioxolano-ethylamines is reported. In Armyanskii Khimicheskii Zhurnal 1968, 21, 509-514, the synthesis of benzodioxan derivatives is described as possible adrenolytic substances. In WO 96/20191, the preparation of 3-(N-aryl and N-heterocyclylaminomethyl)-indole derivatives are described and their use against CNS diseases. In FR patent 2.181.559 indole derivatives are described and their use as anticonvulsant and analgesic agents. In WO 94/26738 benzofuranylurea derivatives and analogues were described as ACAT-inhibitors. In EP 534246 benzylaminoderivatives are described and the use as antiarrhythmic agents. In WO 01/12604, 2-pyridyl derivatives are described as fungicides.
Biological Background
It is well known that sodium channels play an important role in the neuronal network by transmitting electrical impulses rapidly throughout cells and cell networks, thereby coordinating higher processes ranging from locomotion to cognition. These channels are large transmembrane proteins, which are able to switch between different states to enable selective permeability for sodium ions. For this process an action potential is needed to depolarize the membrane, and hence these channels are voltage-gated. In the past few years a much better understanding of sodium channels and drugs interacting with them has been developed.
It has become clear that a number of drugs having an unknown mechanism of action actually act by modulating sodium channel conductance, including local anesthetics, class I antiarrhythmics and anticonvulsants. Neuronal sodium channel blockers have found application with their use in the treatment of epilepsy (phenyloin and carbamazepine), bipolar disorder (lamotrigine), preventing neurodegeneration, and in reducing neuropathic pain. Various anti-epileptic drugs that stabilize neuronal excitability are effective in neuropathic pain (gabapentin).
In addition, an increase in sodium channel expression or activity has also been observed in several models of inflammatory pain, suggesting a role of sodium channels in inflammatory pain.
Calcium channels are membrane-spanning, multi-subunit proteins that allow controlled entry of calcium ions into cells from the extracellular fluid. Commonly, calcium channels are voltage dependent and are referred to as voltage sensitive calcium channels (VSCC). VSCCs are found throughout the mammalian nervous system, where they regulate such varied activities as cellular excitability, transmitter release, intracellular metabolism, neurosecretory activity and gene expression. All “excitable” cells in animals, such as neurons of the central nervous system (CNS), peripheral nerve cells, and muscle cells, including those of skeletal muscles, cardiac muscles and venous and arterial smooth muscles, have voltage dependent calcium channels. Calcium channels have a central role in regulating intracellular calcium ions levels that are important for cell viability and function. Intracellular calcium ion concentrations are implicated in a number of vital processes in animals, such as neurotransmitter release, muscle contraction, pacemaker activity, and secretion of hormones. It is believed that calcium channels are relevant in certain disease states. A number of compounds useful in treating various cardiovascular diseases in mammals, including humans, are thought to exert their beneficial effects by modulating functions of voltage dependant calcium channels present in cardiac and/or vascular smooth muscle. Compounds with activity against calcium channels have also been implicated for the treatment of pain. In particular N-type calcium channels (Cav2.2), responsible for the regulation of neurotransmitters, are thought to play a significant role in nociceptive transmission, both due to their tissue distribution as well as from the results of several pharmacological studies. This hypothesis has been validated in the clinic by Zinocotide, a peptide derived from the venom of the marine snail, Conus Magus. A limitation in the therapeutic use of this peptide is that it has to be administered intrathecally in humans (Bowersox S. S. and Luther R. Toxicon, 1998, 36, 11, 1651-1658).
Monoamine oxidase (MAO) is an integral protein of the outer mitochondrial membrane and plays a major role in the in vivo inactivation of biogenic and diet-derived amines in both the CNS and in peripheral neurons and tissues. Two MAO enzymes are distinguished on the basis of their substrate preferences and sensitivity to inhibition by the MAO inhibitor, clorgyline:                MAO type A (MAO-A) which in the human CNS is responsible for the deamination of serotonin and noradrenaline. The highest MAO-A concentrations are in the catecholaminergic neurons of the locus ceruleus;        MAO-B which is responsible mainly for the catabolism of dopamine. In contrast to the rat brain, MAO-B is the major form in the human and guinea pig CNS. The highest MAO-B concentrations are in the serotoninergic neurons of the raphe nucleus and posterior hypothalamus. The nigral MAO-B is located primarily in glial cells.        
MAO-B (but not MAO-A) activity in CNS increases with age in both humans and animals, perhaps as a result of the glial cell proliferation associated with neuronal loss. Increased MAO-B levels in Alzheimer's plaques have also been reported. Increased blood platelet MAO-B activity has been reported in both Alzheimer's (AD) and Parkinson's Disease (PD). MAO-B activity was reduced by 40% in the brain of smokers: tobacco use is associated both with psychiatric disease and with a reduced risk for PD.
Most currently investigated MAO-B inhibitors are irreversible. The inhibition is very persistent (weeks), as its effects can only be overcome by de novo synthesis of the enzyme. Interest in the MAO-B inhibition was initially stimulated by the desire to elevate the reduced striatal DA concentrations characteristic of PD. As increased DA concentration in the synaptic cleft would be expected as the primary effect of treatment with a selective MAO-B inhibitor. In PD, the need to supply the DA precursor L-Dopa, the golden standard PD therapy, should thus be reduced. This is desirable, as L-Dopa, despite the excellent initial improvement achieved, is associated in the longer term with increasingly severe side effects, including motors fluctuations, dyskinesia and dystonia.
In addition to loss of cholinergic neurons, there is a decrease in the levels of the DA, noradrenaline and serotonin in the brains of AD patients. MAO-B activity is significantly increased in the platelets and selected brain regions of AD patients. MAO-B inhibitors may act by both reducing the formation of oxygen radicals and preventing the breakdown of monoamines and thus elevating their level in the brain of AD patients.
Promising results using MAO-B inhibitors were reported also for the treatment of narcolepsy, Tourette's syndrome/attention deficit disorders, negative symptoms of schizophrenia, drug addiction and obesity.
All together these findings indicate that compounds with sodium and/or calcium channel blockade and/or MAO-B inhibition have a high therapeutic potential in preventing, alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, urologic, metabolic and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.
There are many papers and patents which describe sodium channel and/or calcium channel modulators or antagonists and/or MAO-B inhibitors for the treatment or modulation of a plethora of disorders, such as their use as local anesthetics, antiarrhythmics, antiemetics, antimanic depressants, agents for the treatment of unipolar depression, cardiovascular diseases, urinary incontinence, diarrhea, inflammation, epilepsy, neurodegenerative conditions, nerve cell death, anticonvulsants, neuropathic pain, migraine, acute hyperalgesia and inflammation, renal disease, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, urinary tract disorders, gastrointestinal motility disorders, premature labour, obesity. A largely incomplete list is shown below.
An extensive and thorough prior art overview is reported in WO 03/057219 (and references therein); a further selection of prior art is reported in the following references: Alzheimer, C. Adv. Exp. Med. Biol. 2002, 513, 161-181; Vanegas, H.; Schaible, H. Pain 2000, 85, 9-18; U.S. Pat. No. 5,051,403; U.S. Pat. No. 5,587,454; U.S. Pat. No. 5,863,952; U.S. Pat. No. 6,011,035; U.S. Pat. No. 6,117,841; U.S. Pat. No. 6,362,174; U.S. Pat. No. 6,380,198; U.S. Pat. No. 6,420,383; U.S. Pat. No. 6,458,781; U.S. Pat. No. 6,472,530; U.S. Pat. No. 6,518,288; U.S. Pat. No. 6,521,647; WO 97/10210; WO 03/018561; WO 01/12176; WO 96/37199; U.S. Pat. No. 6,210,706.